Since the initial proposal of TNBC at the beginning of this century, substantial progress has been made in identifying therapeutic targets and more detailed tumor classification [2]. However, few studies on hospice care, patient perspective, surgical treatment of metastasis, and economics are available. Future research will focus on applying new technologies to understand the complex system of TNBC and finding more specific therapeutic targets. However, the recurrence of TNBC after long-term survival still presents new challenges for its clinical management. TNBC is currently undergoing a large number of clinical trials. The rapid clinical progress of TNBC suggests that TNBC is an excellent pioneering area in tumor research and will provide an excellent example for the diagnosis and treatment of other tumors.
It is well-known that TNBC is substantially heterogeneous. Therefore, it is necessary to classify TNBC into multiple subtypes further [15, 16]. The successful subtyping provides a solid theoretical basis for the precision therapy of TNBC [17]. Gene sequencing technology allows us to fully understand the mutation rate of TNBC, which is about 1.68bp/Mb [18]. Mutations occur in genes in multiple key signaling pathways such as PI3K/Akt/mTOR pathway, RAS/RAF/MEK pathway, JAK/STAT pathway, DNA repair pathway, and cell cycle checkpoint [19–21]. Therefore, a variety of drugs targeting the signal pathways are currently undergoing clinical trials. Some inhibitors have been used as potential medications for TNBC treatment, including PI3K, MEK, PARP, EGFR, VEGF, and AR inhibitors [22]. On the other hand, studies on operations and radiotherapy, especially for re-operations related to local-regional recurrence risk or distant metastasis, were rarely reported. Actually, many studies suggest that surgery has an essential role in treating distant metastases of cancers, such as colorectal cancer [23]. In addition, many studies on other kinds of cancers, including pancreatic cancer and colorectal cancer, demonstrated that the tumor microenvironment, especially the extracellular matrix, has been found to play an essential role in cancer metastasis, local recurrence, and chemotherapeutic drug resistance [23]. Many potential drugs are used due to their ability to target the extracellular matrix, such as PEGPH20 (an enzyme that targets matrix hyaluronic acid), pegilodecakin (a PEGylated IL-10) [25, 26]. However, so far, the study on extracellular matrix in TNBC is insufficient. It is hoped that the study on TNBC extracellular matrix is likely to play an essential role in the future.
In the present study, we quantitatively analyzed all 5,097 publications on TNBC through multiple machine learning algorithms for the first time. We found that the research on TNBC mainly focuses on three clusters: TNBC treatment plan research, the new biomarkers research and the regulation mechanism for TNBC aggressive behavior. In the cluster of regulation mechanisms for TNBC aggressive behavior, we found an exciting part of a close connection between hypoxia and imaging. Hypoxia refers to malignant cells' inability to receive enough oxygen as the tumor expands [27]. Low oxygen levels stabilize hypoxia-inducible factors (HIFs), which in turn regulates the transcriptional activation of a group of genes, allowing cells to survive under hypoxic conditions [28]. On the one hand, we speculate that these manifestations will be evident in imaging, which will improve the early diagnosis of TNBC and the detection of possible distant metastases in the future. On the other hand, the hypoxic properties of TNBC bring new hopes for treatment with the aid of imaging such as MRI and ultrasound, which are highly sensitive to the hypoxic microenvironment of TNBC. Studies have found that carbonic anhydrase-IX-directed albumin nanoparticles have a deadly effect on hypoxia-mediated T lymphocyte-negative breast cancer cells and can be visualized in a real-time fashion [29]. At present, new hypoxia-inducible factor-2α antagonists such as PT2385 have shown encouraging results in phase I clinical trials of previously treated advanced clear cell renal cell carcinoma [30]. More than two-thirds of patients reported clinical benefits with acceptable toxicity profiles. PT2977, a more effective second-generation hypoxia-inducible factor-2α antagonist, is the subject of several ongoing solid tumor clinical trials (NCT02974738, NCT03634540, NCT03401788) [31]. With the in-depth study on TNBC hypoxia aided by its imaging, developing new treatment strategies for cancers is possible.
Although the research on TNBC has made significant progress in many aspects, the present research also found some research deficiencies on TNBC. First of all, there are considerable differences in geographic-related research. It has been found that individuals with different genetic backgrounds have different responses to TNBC, survival rates, and mortality rates [32, 33]. However, the global distribution of TNBC research is uneven, and the research on populations with different genetic backgrounds is insufficient. For example, only 61 publications in the PubMed database are related to African descent. Strengthening TNBC research on individuals with different genetic backgrounds could facilitate our understanding of TNBC from different perspectives [34]. Secondly, there is a lack of research on TNBC from patient's perspectives, e.g., health economics, hospice care. Although, at present, the 5-year overall survival rate of most tumors has been greatly improved, helping tumor patients with psychological issues re-enter society will become a new important research topic [35]. Compared with other breast cancer subtypes, TNBC patients are more likely to relapse and metastasize, resulting in more significant pressure, both mentally and economically, on patients and their families. Studies on patients with more prolonged survival can better understand TNBC and even other long-term survival tumors [36]. We will face more challenges for patients with a long survival period of 5–10 years in the future [37].
There are some limitations in the present study. Firstly, besides PubMed, several other databases, including Scopus, Web of Science, and Embase, could be used for bibliometric research. Although PubMed contains the highest quality peer-reviewed research and excludes irrelevant, non-peer-reviewed papers, the literature will provide detailed and comprehensive knowledge if other databases are explored simultaneously. Secondly, we considered that all publications tend to publish more positive research results. Negative results and clinical participants’ perspectives are naturally more difficult to be published.
In summary, with the further expansion of the publishing industry and the explosion of the number of information dimensions, the vast array of documents will make the understanding of TNBC more difficult. Researchers are lost in the information as it is not easy to obtain the information they want. With the development of complete medical record texts, publication databases, and improved algorithms, it is reasonable for machine learning to play a more active auxiliary role in future clinical practice. Machine learning and natural language processing may be an extremely effective new tool for scientists, who will extract objective and comprehensive clues from large amounts of data. The data presented in this study will hopefully help scientists understand the current status of TNBC research and design more relevant basic and clinical research projects.